Award details

The role of miR-128, a novel microRNA in somite development

Reference	BB/K003437/1
Principal Investigator / Supervisor	Professor Andrea Munsterberg
Co-Investigators / Co-Supervisors
Institution	University of East Anglia
Department	Biological Sciences
Funding type	Research
Value (£)	363,444
Status	Completed
Type	Research Grant
Start date	11/02/2013
End date	10/02/2016
Duration	36 months

Abstract

We are interested in the molecular signalling networks controlling early events in vertebrate embryogenesis. Developing vertebrate somites have served as paradigm to investigate the mechanisms underlying cell fate choices of mesoderm progenitor cells, that can give rise to a number of different lineages. We focus here on the determination of multi-potent embryonic progenitor cells towards the skeletal muscle fate and the early steps that control the skeletal muscle differentiation programme. We use mainly chick embryos, which are easily accessible and obtained after incubating fertilized eggs, thus reducing the number of animals needed. Experiments in chick are complemented by comparative expression analyses in mouse embryos and by cell based approaches using the well-characterized C2C12 myogenic cells. This project will investigate the importance of a novel microRNA, miR-128 whose function in mesoderm is poorly understood, for the specification and differentiation of myogenic progenitors. Preliminary work showed expression of miR-128 in early somites, which will give rise to the dermomyotome and myotome, containing skeletal muscle progenitor cells and committed myoblasts. We have compiled a list of candidate targets and propose genome-wide identification of targets, which will be experimentally validated. Confirmed targets will be further investigated, using established methods in vivo and in cell based assays. The initial focus will be on a gene called Klhl31, a novel Wnt antagonist, for which we have pilot data. The precise roles for microRNAs in embryonic development are not completely understood and our knowledge of how they affect skeletal muscle cell fate commitment is cryptic. This project will address this shortfall, we aim to make a significant contribution to our understanding of microRNA function during myogenesis and this will also provide more general insights into the fundamental mechanisms employed in cellular programming.

Summary

Multi-cellular organisms contain many distinct cell types with very specialized functions. For example, we need skeletal muscle to be able to move while our skin prevents dehydration and protects us from injury and infections. Amazingly all these different cells arise from a single cell, the fertilized egg. The development of an embryo begins when the egg starts dividing to give rise to many cells. Different cells are specified during embryonic development - they are told what to become by molecular signals that act in the early embryo. These signals often cause specific genes to be switched 'on' or 'off'. If a gene is 'on' it is expressed, which means that it is actively transcribed from the DNA in the nucleus of the cell. During the process of transcription, DNA is copied into RNA. These RNA transcripts typically encode proteins and are translated by a complex cellular machinery. Proteins are the 'movers and shakers' in a cell, they define a cell and they have specific jobs to do. For example, the contraction of skeletal muscle is mediated by fast and slow contractile fibers (made up of proteins). Muscle is a very plastic tissue and depending on whether you train to be a sprinter or a marathon runner different types of muscle proteins will be expressed. Muscle also has the ability to repair itself (to regenerate) for example after wearing a cast muscle mass is lost, but it builds up again quickly when the muscle is used again. We are interested in the molecules that control the development of muscle in an embryo, it is known that some of these factors are also used when muscle needs to regenerate, for example after injury or long-term bed rest. Our studies focus on a class of RNA molecules, which are not translated to make proteins. Here the RNA molecule itself has important functions. These non-coding RNAs were discovered recently and because they are very small, they were called 'micro'RNAs (miRs). They have been found in plants and animals, which means, that they are part of the most basic machinery of life with a very important and fundamental job to do in all cells - in fact microRNAs control whether or not other coding RNAs are translated into protein. A lot of research is being done, to help understand how this is happening and to uncover what type of cellular processes are controlled in this fashion. Our research investigates how cells become different from one another in a developing vertebrate embryo. In particular, we study the genes and molecules that control the decision of a cell to differentiate into skeletal muscle from a multi-potent precursor, as opposed to into bone for example. We recently discovered an important novel function for a muscle specific microRNA in embryonic muscle. We also figured out how the production of the microRNA itself is being switched 'on' or 'off'. We identified the genes controlled by the microRNA (the 'targets') and we are beginning to understand how they in turn affect skeletal muscle. There are many additional microRNAs in developing muscle cells and we previously identified some of them using modern sequencing technology. We now want to understand what the role of these microRNAs is. Ideally we want to identify all the microRNAs and their target genes that play a role in skeletal muscle. Overall we will learn how an embryo makes normal, healthy, working muscle and this will in the long-term benefit people who suffer from various conditions that affect muscle health or help to alleviate age related muscle-loss.

Impact Summary

The musculoskeletal system is essential for healthy living and it has the ability to repair itself using stem cells. Muscle repair works less effectively as we age gradually leading to a decrease in quality of life. We study how muscle develops in embryos and this project will focus on a novel microRNA. (1) The potential therapeutic benefit of microRNAs has been recognized as they are small and can inhibit protein expression. We will investigate how they control the commitment of a progenitor ('stem') cell to the skeletal muscle fate. Because many embryonic signals are re-employed during muscle regeneration/repair, results from this work will impact on the mechanisms involved in the maintenance of healthy muscle. This could be important for future biomedical applications and thus will be relevant to the pharmaceutical industry or biotech companies. (2) MicroRNAs and their targets may also be useful biomarkers for different skeletal muscle conditions. Although this project does not directly aim to discover such biomarkers we will examine the molecular network of regulators involved in myogenic differentiation and increased understanding of the players involved may therefore become relevant for clinicians and diagnostic applications in the future. (3) We also anticipate to impact on the fields of muscle biology, developmental biology and potentially stem cell research by providing skilled researchers who will apply key techniques to investigate gene function in vivo. This is important in the post-genomic era where most genes, coding and non-coding, have now been discovered, but their detailed functions are still incompletely understood. Advances in this area of bioscience will also underpin future economic success. (4) In addition to the potential practical benefits illustrated above, there will be benefits and outcomes relating to the increase of knowledge and understanding of biological mechanisms and phenomena. This will impinge on the education of students, their teachers as well as the general public, who are highly appreciative of the advances made in recent years in the areas of biotechnology and biomedicine.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Stem Cells, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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